The long range objective of this Program Project is to identify the processes through which normal growth control is altered to bring about neoplastic transformation. Cell proliferation is regulated by a complex set of controls that involve stimulation-inhibition of growth and regulation of differentiation. The overall focus of this program will be to investigate the basic regulatory control mechanisms through which growth inhibitory peptides and inducers of differentiation modulate cell proliferation. All projects will advance our understanding of normal growth and the development of cancer. The program is composed of projects that propose the use of biological, biochemical, and molecular technologies and transgenic mice. Project 1 will use molecular biology to characterize specific gene expression regulating differentiation. Project 2 seeks to determine if the resistance to the normal growth inhibition of TGF Beta is controlled by the expression of a specific set of genes. Project 3 will use molecular biology techniques to test the hypothesis that the inhibitory effects of TGF Beta on the growth of mouse keratinocytes are brought about by an increase or decrease in the expression of a specific set of gene products. Project 4 will investigate the characteristics and function of c-myc gene products of keratinocyte and erythroid cells in differentiation and growth inhibition. Project 5 seeks to explore the apparent requirement for a decrease in c- myc expression to allow human myeloid differentiation. Project 6 will study the role of TGF Beta and Vg-r genes in the regulation of normal embryonic development, and will use transgenic mice to establish genetic models for testing the in vivo function of the Vg-r gene. The six individual research projects in this program will be supported by four core units. One core (Core A) will provide centralized administrative support. Core B will provide microchemistry, including synthesis and sequencing of peptides and nucleotides. Core C will provide cells and molecular biological services. The last core (Core D) will provide the transgenic mouse facility required in several of the proposed projects. This program brings together a skilled group of investigators and projects that integrate into a focused but broad experimental unit designed to characterize the processes that alter normal growth control and lead to the neoplastic growth state.